The impact of cancer patient pathway on timing of radiotherapy and survival: a cohort study in glioblastoma patients.

PURPOSE: Glioblastoma (GBM) is an aggressive brain tumor in which primary therapy is standardized and consists of surgery, radiotherapy (RT), and chemotherapy. However, the optimal time from surgery to start of RT is unknown. A high-grade glioma cancer patient pathway (CPP) was implemented in Norway in 2015 to avoid non-medical delays and regional disparity, and to optimize information flow to patients. This study investigated how CPP affected time to RT after surgery and overall survival. METHODS: This study included consecutive GBM patients diagnosed in South-Eastern Norway Regional Health Authority from 2006 to 2019 and treated with RT. The pre CPP implementation group constituted patients diagnosed 2006-2014, and the post CPP implementation group constituted patients diagnosed 2016-2019. We evaluated timing of RT and survival in relation to CPP implementation. RESULTS: A total of 1212 patients with GBM were included. CPP implementation was associated with significantly better outcomes (p < 0.001). Median overall survival was 12.9 months. The odds of receiving RT within four weeks after surgery were significantly higher post CPP implementation (p < 0.001). We found no difference in survival dependent on timing of RT below 4, 4-6 or more than 6 weeks (p = 0.349). Prognostic factors for better outcomes in adjusted analyses were female sex (p = 0.005), younger age (p < 0.001), solitary tumors (p = 0.008), gross total resection (p < 0.001), and higher RT dose (p < 0.001). CONCLUSION: CPP implementation significantly reduced time to start of postoperative RT. Survival was significantly longer in the period after the CPP implementation, however, timing of postoperative RT relative to time of surgery did not impact survival.

Incidence and outcome of pseudoprogression after radiation therapy in glioblastoma patients: A cohort study.

Background: Differentiating post-radiation MRI changes from progressive disease (PD) in glioblastoma (GBM) patients represents a major challenge. The clinical problem is two-sided; avoid termination of effective therapy in case of pseudoprogression (PsP) and continuation of ineffective therapy in case of PD. We retrospectively assessed the incidence, management, and prognostic impact of PsP and analyzed factors associated with PsP in a GBM patient cohort. Methods: Consecutive GBM patients diagnosed in the South-Eastern Norway Health Region from 2015 to 2018 who had received RT and follow-up MRI were included. Tumor, patient, and treatment characteristics were analyzed in relationship to re-evaluated MRI examinations at 3 and 6 months post-radiation using Response Assessment in Neuro-Oncology criteria. Results: A total of 284 patients were included in the study. PsP incidence 3 and 6 months post-radiation was 19.4% and 7.0%, respectively. In adjusted analyses, methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter and the absence of neurological deterioration were associated with PsP at both 3 (p < .001 and p = .029, respectively) and 6 months (p = .045 and p = .034, respectively) post-radiation. For patients retrospectively assessed as PD 3 months post-radiation, there was no survival benefit of treatment change (p = .838). Conclusions: PsP incidence was similar to previous reports. In addition to the previously described correlation of methylated MGMT promoter with PsP, we also found that absence of neurological deterioration significantly correlated with PsP. Continuation of temozolomide courses did not seem to compromise survival for patients with PD at 3 months post-radiation; therefore, we recommend continuing adjuvant temozolomide courses in case of inconclusive MRI findings.

Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden.

INTRODUCTION: The use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase (IDH)-mutated diffuse gliomas grade 2-3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life. METHODS AND ANALYSIS: PRO-GLIO (PROton versus photon therapy in IDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18-65 years with IDH-mutated diffuse gliomas grade 2-3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints. ETHICS AND DISSEMINATION: To implement proton therapy as part of standard of care for patients with IDH-mutated diffuse gliomas grade 2-3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05190172).

Astrocytoma (CNS WHO grade 4), IDH-mutant with co-occurrence of BRAF p.V600E mutation, and homozygous loss of CDKN2A.

Molecular alterations nowadays play a crucial role in the diagnosis of brain tumors. Some of these alterations are associated with outcome and/or response to treatment, including sequence variants of isocitrate dehydrogenase (IDH) at position p.R132 or p.R172. Such IDH variants have so far been described in histone H3-wildtype primary brain tumors only in adult-type diffuse gliomas and are associated with a better outcome compared to their IDH-wildtype counterpart, the glioblastoma. Moreover, homozygous loss of CDKN2A and/or CDKN2B in IDH-mutant astrocytomas shortens the median overall survival regardless of histological features of malignancy. Such tumors are therefore considered to be aggressive and graded as WHO central nervous system (CNS) grade 4 lesions. The coexistence of an IDH-sequence variation and a BRAF p.V600E alteration has only rarely been described in diffuse astrocytomas. Due to the small number of cases, little is known about such neoplasms in terms of clinical behavior and response to treatment. Herein we describe the first case, to our knowledge, of an astrocytoma (CNS WHO grade 4), IDH-mutant, and BRAF p.V600E-mutant with homozygous deletion of CDKN2A. Pathologists should be aware that such an expression profile does exist even in WHO CNS grade 4 astrocytomas, IDH-mutant, and are encouraged to test for the BRAF p.V600E sequence variant as such an alteration may provide additional treatment options.

Survival in a consecutive series of 467 glioblastoma patients: Association with prognostic factors and treatment at recurrence at two independent institutions.

Therapy of recurrent glioblastoma (GBM) is challenging due to lack of standard treatment. We investigated physicians' treatment choice at recurrence and prognostic and predictive factors for survival in GBM patients from Norway's two largest regional hospitals. Clinicopathological data from n = 467 patients treated at Haukeland and Oslo university hospitals from January 2015 to December 2017 was collected. Data included tumour location, promoter methylation of O6 methylguanine-DNA methyltransferase (MGMT) and mutation of isocitrate dehydrogenase (IDH), patient age, sex, extent of resection at primary diagnosis and treatment at successive tumour recurrences. Cox-proportional hazards regression adjusting for multiple risk factors was used. Median overall survival (OS) was 12.1 months and 21.4% and 6.8% of patients were alive at 2 and 5 years, respectively. Median progression-free survival was 8.1 months. Treatment at recurrence varied but was not associated with difference in overall survival (OS) (p = 0.201). Age, MGMT hypermethylation, tumour location and extent of resection were independent prognostic factors. Patients who received 60 Gray radiotherapy with concomitant and adjuvant temozolomide at primary diagnosis had 16.1 months median OS and 9.3% were alive at 5 years. Patients eligible for gamma knife/stereotactic radiosurgery alone or combined with chemotherapy at first recurrence had superior survival compared to chemotherapy alone (p<0.001). At second recurrence, combination chemotherapy with or without bevacizumab were both superior to no treatment. Treatment at recurrence differed between the institutions but there was no difference in median OS, indicating that it is the disease biology that dictates patient outcome.

SMART syndrome: two cases highlighting a complex and rare complication of brain irradiation.

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare complication of radiotherapy with complex neurological impairment. Patients present with neurological symptoms and signs such as migraine, hemianopsia, hemiplegia, aphasia and/or seizures-without recurrence of neoplastic disease. In this report, we describe SMART syndrome in two adult patients 4 and 14 years following brain irradiation, respectively.